Drug resistance to topoisomerase directed chemotherapy in human multiple myeloma

2008 2008

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Abstract (summary)

Human multiple myeloma is an incurable hematological malignancy characterized by the proliferation of plasma cells in the bone marrow. Myeloma represents approximately 20% of all blood cancers. In this research we have explored examples of both intrinsic and acquired drug resistance in myeloma.

Topoisomerases are enzymes that are critical for cell division, especially in rapidly dividing cells such as are found in cancer. Topoisomerase poisons are a common group of drugs that are used to treat cancer. Topoisomerase I and II poisons used in the treatment of multiple myeloma include topotecan, mitoxantrone, doxorubicin, and etoposide.

In order for topoisomerase drugs to be effective, the enzyme must be in direct contact with the DNA. In chapters one and two we examined the export of topoisomerase II alpha from the nucleus as a mechanism of drug resistance. High density cells, similar to those found in the bone marrow, export topoisomerase II alpha from the nucleus to the cytoplasm, rendering the cell drug resistant. We found that blocking nuclear export using the CRM1 inhibitor ratjadone C, or CRM1 specific siRNA, could sensitize high density cells to topoisomerase drugs. Sensitization to topoisomerase inhibitors was correlated with increased topoisomerase/DNA complexes and increased DNA strand breaks. This method of sensitizing human myeloma cells suggests a new therapeutic approach to this disease.

In chapter three we examined the role of the molecular transporter ABCG2 in drug resistance in multiple myeloma. We found that ABCG2 expression in myeloma cell lines increased after exposure to topotecan or doxorubicin. Myeloma patients treated with topotecan had an increase in ABCG2 mRNA and protein expression after drug treatment and at relapse. We found that expression of ABCG2 is regulated, at least in part, by promoter methylation both in cell lines and in patient plasma cells. Demethylation of the promoter increased ABCG2 mRNA and protein expression. These findings suggest that ABCG2 is expressed and functional in human myeloma cells, regulated by promoter methylation, affected by cell density, upregulated in response to chemotherapy, and may contribute to drug resistance.

Indexing (details)

Molecular biology;
0307: Molecular biology
0419: Pharmacology
0992: Medicine
Identifier / keyword
Health and environmental sciences; Biological sciences; ABCG2; CRM1; Cell cycle regulators; Drug resistance; Multiple myeloma; Nuclear export; Topoisomerase; Tumor suppressors
Drug resistance to topoisomerase directed chemotherapy in human multiple myeloma
Turner, Joel G.
Number of pages
Publication year
Degree date
School code
DAI-B 69/08, Dissertation Abstracts International
Place of publication
Ann Arbor
Country of publication
United States
Sullivan, Daniel M.; Garey, James R.
University of South Florida
University location
United States -- Florida
Source type
Dissertations & Theses
Document type
Dissertation/thesis number
ProQuest document ID
Database copyright ProQuest LLC; ProQuest does not claim copyright in the individual underlying works.
Document URL
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